Diabetes represents a major healthcare problem for the United States. With more people becoming overweight or obese each year, the total number of people affected by diabetes in the United States is expected to increase and result in significantly higher medical costs. PPARG is a ligand-regulated nuclear receptor transcription factor and a validated molecular target for insulin sensitizing drugs. Safety concerns have severely restricted clinical use of PPARG-targeted drugs due to serious side effects, including loss of bone, fluid retention and congestive heart failure. Recent work has led to an understanding that ligands differentially affect the structural conformation of two distinct surfaces used by PPARG to interact with different functional interaction partners. It is thought that targeted stabilization of one surface over another can lead to the development of a new generation of PPARG-binding anti-diabetic drugs with fewer unwanted side effects. A central tenet driving current PPARG drug development is that synthetic ligands compete with natural endogenous ligands, including fatty acids and lipids, for binding to a canonical ligand-binding pocket in the core of the ligand-binding domain to pharmacologically regulate PPARG activity. Our preliminary work shows that many synthetic ligands that were designed to bind to the canonical ligand-binding pocket in PPARG can also bind to an alternate binding site. Detailing the structure and function of this alternate binding ste could improve development of more potent drugs that target this site if studies indicate it enhances anti-diabetic efficacy, or limit binding to this site if it contributes to side effects. Uing a multidisciplinary approach, combining structural and chemical biology with biochemical and cellular assays, we will characterize the effects of alternate-site ligand binding on PPARG structure, function and cellular outcomes associated with anti-diabetic efficacy and side effects. Outcomes from these studies will provide the first structural and functional understanding of alternate-site ligand binding to PPARG. These findings will expand the general understanding of PPARG function and regulation of PPARG activity by ligands. This knowledge could lead to the development of improved anti-diabetic PPARG-targeted drugs with fewer unwanted side effects.